期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 -, 页码 705-721出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.01.016
关键词
Antiproliferative; Beta-lactam; Combretastatin A-4; Prodrug; Solubility; Tubulin
资金
- Health Research Board
- Trinity College Dublin
The synthesis and biochemical activities of novel water-soluble beta-lactam analogues of combretastatin A-4 are described. The first series of compounds investigated, beta-lactam phosphate esters 7a, 8a and 9a, exhibited potent antiproliferative activity and caused microtubule disruption in human breast carcinoma-derived MCF-7 cells. They did not inhibit tubulin polymerisation in vitro, indicating that biotransformation was necessary for their antiproliferative and tubulin binding effects in MCF-7 cells. The second series of compounds, beta-lactam amino acid amides (including 10k and 11l) displayed potent antiproliferative activity in MCF-7 cells, disrupted microtubules in MCF-7 cells and also inhibited the polymerisation of tubulin in vitro. This indicates that the beta-lactam amides did not require metabolic activation to have antiproliferative effects, in contrast to the phosphate series. Both series of compounds caused mitotic catastrophe and apoptosis in MCF-7 cells. Molecular modelling studies indicated potential binding conformations for the beta-lactam amino acid amides 10k and 11l in the colchicine-binding site of tubulin. Due to their aqueous solubility and potent biochemical effects, these compounds are promising candidates for further development as microtubule-disrupting agents. (C) 2013 Elsevier Masson SAS. All rights reserved.
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